Substance delivery device

ABSTRACT

A system being suitable for being secured substantially adjacent to a surface of a subject so as to effect delivery of at least one substance through the surface and into the subject. The system includes at least one aperture for receiving at least one ultrasonic transmission. The at least one substance is releasably secured substantially adjacent to the at least one aperture. A sonic member is disposed with respect to the at least one aperture so as to communicate the at least one transmission to the at least one substance so as to effect the delivery of the at least one substance through the surface of the subject.

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Patent applicationserial no. U.S. Patent application serial No. 60/351,191, filed Jan. 25,2002 and entitled Wearable, portable sonic applicator for inducing therelease of bioactive compounds from internal organs and U.S. Patentapplication serial no. U.S. Patent application serial No. 60/349,061,filed Jan. 16, 2002 and entitled “SUBSTANCE DELIVERY DEVICE” and, and isa continuation-in-part of: U.S. patent application Ser. No. 09/939,506,filed Aug. 24, 2001 and entitled “SUBSTANCE DELIVERY SYSTEM”; U.S.patent application Ser. No. 09/939,435, filed Aug. 24, 2001 and entitled“ULTRASONICALLY ENHANCED SUBSTANCE DELIVERY METHOD”; and, U.S. patentapplication Ser. No. 09/939,507, filed Aug. 24, 2001, entitled““ULTRASONICALLY ENHANCED SUBSTANCE DELIVERY SYSTEM AND DEVICE”, theentire disclosures of which are each respectively hereby incorporated byreference herein as if being set forth in their respective entireties.

FIELD OF THE INVENTION

[0002] The present invention relates generally to substance deliverysystems, and particularly to ultrasonically enhanced substance deliverydevices.

BACKGROUND OF THE INVENTION

[0003] Generally, transdermal drug delivery systems employ a medicateddevice or patch which is affixed to the skin of a patient. The patchallows a medicinal compound contained within the patch to be absorbedthrough the skin layers and into the patient's blood stream. Transdermaldrug delivery reduces the pain associated with drug injections andintravenous drug administration, as well as the risk of infectionassociated with these techniques. Transdermal drug delivery also avoidsgastrointestinal metabolism of administered drugs, reduces theelimination of drugs by the liver, and provides a sustained release ofthe administered drug. Transdermal drug delivery also enhances patientcompliance with a drug regimen because of the relative ease ofadministration and the sustained release of the drug.

[0004] Many medicinal compounds are not suitable for administration viaknown transdermal drug delivery systems since they are absorbed withdifficulty through the skin due to the molecular size of the drug or toother bioadhesion properties of the drug. In these cases, whentransdermal drug delivery is attempted, the drug may be found pooling onthe outer surface of the skin and not permeating through the skin intothe blood stream. Once such example is insulin, which has been founddifficult to administer by means of transdermal drug delivery.

[0005] Some of the most critically needed medications are currentlyadministered either by injection or oral dosage forms, which can haveseveral drawbacks. In particular, chemotherapeutic agents areadministered in increased dosages because of their need to survivedegradation in the gastrointestinal tract. Many critical treatments forAIDS require a cocktail of drugs taken orally in solid dosage forms,several times a day to be effective. These medications are not suitablefor administration via known transdermal drug delivery system because ofthe extensive dosing requirement, as well as the inability of the drugmolecule to remain stable in a transdermal form. Moreover, theunsuitability of many drugs for conventional transdermal transfer may bedue to low bioabsorbance of the drug across the skin layers.

[0006] Generally, conventional transdermal drug delivery methods havebeen found suitable only for low molecular weight medications such asnitroglycerin for alleviating angina, nicotine for smoking cessationregimens, and estradiol for estrogen replacement in post-menopausalwomen. Larger molecular medications such as insulin (a polypeptide forthe treatment of diabetes), erythropoietin (used to treat severe anemia)and gamma-interferon (used to boost the immune systems cancer fightingability) are all compounds not normally effective when used withconventional transdermal drug delivery methods.

[0007] However, the use of energy, such as ultrasonic energy, may beused to enhance the transdermal delivery of certain drugs. While theseterms “ultrasound” and “ultrasonic” as used herein have their ordinarymeaning, at least one source has defined “ultrasound” as mechanicalpressure waves with frequencies above 20 kHz, H. Lutz et al., Manual ofUltrasound 3-12 (1984). Ultrasound may be generated by vibrating apiezoelectric crystal or other electromechanical element by passing analternating current through the material. The use of ultrasound toincrease the permeability of the skin to drug molecules has been termedsonophoresis or phonophoresis.

[0008] Previously described methods for using ultrasound to enhancetransdermal drug delivery required the use in a clinical ultrasonicdelivery setting, such as a physician's office, hospital or clinic.Moreover, the time for delivery of measurable amounts into human skinusing these methods ranged from 10 minutes to 24 hours. In this case,the use of ultrasound-transdermal drug delivery treatment may beactually less desirable from a patient administration standpoint than asimple injection. This method is undesirable because of the need for thepatient to visit the clinical setting and to remain on a treatment tablewhile the ultrasound treatment is used to deliver the drug.

[0009] While the use of certain ultrasonic frequencies for the enhancingdelivery of certain drugs in certain applications is known, results insuch applications have been largely disappointing. In many cases thedrug delivery pathway utilized enabled initial quantities of a drug topermeate the skin, but as longer periods of ultrasound were applied tothe same location on the skin the delivery rate dropped off or wasreduced to zero.

[0010] The exposure to ultrasound has been either continuous or pulsedto reduce heating of biological membranes. The depth of penetration ofultrasonic energy into living soft tissue is inversely proportional tothe frequency, thus high frequencies have been suggested to improve drugpenetration through the skin by concentrating the effect in theoutermost skin layer, the stratum corneum. Pharmaceutical agents undersonic transdermal delivery may require variable frequencies andintensities in order to deliver therapeutic quantities of drugs topatients. Variables such as fat content and mass of a particularpatient's tissue, through which the drug will be delivered, may vary thefrequency and intensity requirements to obtain an effective dosingregimen.

[0011] Portable programmable devices and methods for ultrasonicallyenhancing substance delivery through a surface of a subject have notbeen disclosed. Because of the inefficiencies and lack of safety of theprevious ultrasonic methods, no useful device has been proposed for thetransdermal delivery of drugs with an ultrasonic assist.

[0012] Little effort has in the past been focused upon the design of atransdermal patch suitable for ultrasonic drug transport. The use of anultrasonic applicator or sonicator applied to skin tissue hasconventionally been employed with a pool of a target drug laying underthe tip of the transducer and laying upon the skin surface. This methodof ultrasonic drug delivery is not believed to be feasible in acommercial application. Other examples in which the skin ispre-sonicated and then a patch is placed over the sonicated skin areaemploy a passive drug delivery based upon the concept of inducedincreased permeability as effected by the ultrasonic transmission. Thisalso is commercially non-feasible because of the length of time neededto pre-sonicate the skin and other factors.

[0013] In view of the foregoing problems and/or deficiencies, thedevelopment of a device for safely enhancing the permeability of theskin for noninvasive drug delivery in a more rapid time frame would be asignificant advancement in the art. It would be another significantadvancement in the art to provide an ultrasonic programmable device andmethod that can be used with a drug-containing patch. In addition,patient mobility, coupled with sustained release of a broad range ofdrugs, until now, has remained an elusive goal of transdermal drugdelivery devices. Thus, the design of a suitable transdermal patch toaccommodate an active ultrasonic transdermal delivery method is helpfulto achieving a commercial ultrasonic drug delivery device.

SUMMARY OF THE PRESENT INVENTION

[0014] A system being suitable for being secured substantially adjacentto a surface of a subject so as to effect delivery of at least onesubstance through the surface and into the subject including: at leastone aperture for receiving at least one ultrasonic transmission, the atleast one substance being releasably secured substantially adjacent tothe at least one aperture; and, a sonic member disposed with respect tothe at least one aperture so as to communicate the at least onetransmission to the at least one substance so as to effect the deliveryof the at least one substance through the surface of the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The present invention will be more readily understood inconnection with the non-limiting, attached figures, wherein:

[0016]FIG. 1 is a transdermal patch with an ultrasonic generator, whichis worn by the patient, as it is placed on the arm of a patient.

[0017]FIG. 2 is an illustration of the structure of human skin.

[0018]FIG. 3 illustrates a transdermal patch wherein transducers areexterior to the patch.

[0019]FIG. 4 illustrates a transdermal patch wherein the patch isconstructed employing a gasket or sealer around the edges of the patch.

[0020]FIG. 5 illustrates an ultrasonic signal, which alternates from asawtooth to a square waveform.

[0021]FIG. 6 illustrates a transdermal patch wherein a transducer orarray of transducers is directly imbedded within the patch.

[0022]FIG. 7 illustrates a transdermal patch wherein a semi-permeablefilm placed on the underside of the patch acts to provide a valvingfunction with the administration of transmitted ultrasound though thepatch.

[0023]FIG. 8 illustrates a patch according to an aspect of the presentinvention.

[0024]FIG. 9 illustrates a transdermal delivery device according to anaspect of the present invention.

[0025]FIG. 10 illustrates a transducer coupler according to an aspect ofthe invention, suitable for use in connection with the device of FIG. 9wherein the transducer coupler is constructed to couple with a cap unitcontaining at least one substance to be delivered.

[0026]FIG. 11 illustrates a cap unit constructed to couple with thetransducer coupler of FIG. 10.

[0027]FIG. 12 illustrates a view of the interior of a cap unit accordingto FIG. 11.

[0028]FIG. 13 illustrates an inner snap ring of a cap unit of FIG. 11.

[0029]FIG. 14 illustrates an outer snap ring of a cap unit of FIG. 11.

[0030]FIG. 15 illustrates a top view of a transdermal delivery assemblyor device according to an aspect of the present invention.

[0031]FIG. 16 illustrates a bottom view of a transdermal deliveryassembly of FIG. 15.

[0032]FIG. 17 illustrates a top view of a transducer coupler suitablefor use in connection with the assembly of FIG. 15 wherein thetransducer coupler is constructed to couple with a cap unit containingat least one substance to be delivered.

[0033]FIG. 18 illustrates a bottom view of the transducer coupler ofFIG. 17.

[0034]FIG. 19 illustrates a top view of an inner ring of a cap unit.

[0035]FIG. 20 illustrates a bottom view of an inner ring of FIG. 20

[0036]FIG. 21 illustrates a top view of an outer ring of a cap unit.

[0037]FIG. 22 illustrates a bottom view of an outer ring of FIG. 21.

[0038]FIG. 23 illustrates an exploded view of an assembly of FIG. 15.

[0039]FIGS. 24A through 31 illustrate achievable results in accordancewith an aspect of the invention.

[0040]FIGS. 32A through 32C illustrate a transdermal delivery deviceaccording to an aspect of the present invention.

[0041]FIGS. 32D and 32E illustrate achievable results in accordance withan aspect of the invention.

[0042]FIG. 32F illustrates a desktop transdermal delivery systemaccording to an aspect of the invention.

[0043]FIG. 32G illustrates a belt-mounted transdermal delivery systemaccording to an aspect of the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] It is to be understood that the figures and descriptions of thepresent invention have been simplified to illustrate elements that arerelevant for a clear understanding of the present invention, whileeliminating, for purposes of clarity, many other elements found insubstance delivery systems. Those of ordinary skill in the art willrecognize that other elements are desirable and/or required in order toimplement the present invention. However, because such elements are wellknown in the art, and because they do not facilitate a betterunderstanding of the present invention, a discussion of such elements isnot provided herein.

[0045] The present invention relates to patches, which may be employedwith an ultrasonic drug delivery device, which is ideally worn by thepatient.

[0046] According to an embodiment of the present invention, atransdermal patch is provided for enhancing transdermal drug delivery bythe use of ultrasound. As used herein, the terms “drug” and “substance”may be used together or interchangeably and may include, but are notlimited to, any substance including, but not limited to, a medicinal ornon-medicinal substance which may be transported through a surface ormembrane, including, but not limited to, tissue and other types ofmembranes. Use of ultrasonics is particularly effective in deliveringlarger pharmaceutically active compounds, wherein the transdermal patchis made to accommodate both the special needs of ultrasonic excitationthrough the patch construct and the delivery of medicinal compoundsstored within the patch.

[0047] According to an embodiment of the present invention, atransdermal delivery device or patch is designed with materials toenable the transmission of ultrasound through the patch, effecting thedelivery of medications stored within the patch, and to be used inconjunction with ultrasonic drug delivery processes. The transdermalpatch may contain a substance, such as, for example, a particularmedication or cocktail of medications for treatment of disease or reliefof pain. A sonic applicator may be placed in the proximity of the patch,such as for example, over the top of the patch or into a pocket in thepatch or may be contained within the patch construction itself. When thesonic applicator is activated by means of an external timing circuitryand driver mechanism or other suitable electronics, the sonic applicatorgenerates an ultrasonic vibration or ultrasonic transmission through thetransdermal patch. The effects of the energy of the ultrasonic signal,including, but not necessarily limited to, the vibration induced withinthe patient's skin, increase the absorption of the medication emanatingfrom the transdermal patch through the skin into the patient'sbloodstream.

[0048] According to an embodiment of the present invention, introductionof an ultrasonic signal to a transdermal patch increases the type ofmedications which can be employed in a transdermal delivery system,including large molecule medications, nutrient solutions, and proteinswhich heretofore were not capable of being delivered through atransdermal system.

[0049] According to an embodiment of the present invention, the use ofan ultrasonic applicator with a transdermal patch provides fullportability in the drug delivery system, as opposed to systems employingultrasound to enhance drug delivery wherein the patient requires theassistance of a health professional, typically at a hospital, doctor'soffice or clinic.

[0050] According to an embodiment of the present invention, the systemcan be programmed to provide steady drug delivery or pulsed timeddelivery at certain medication quantities, providing more flexibilityand control over a particular patients dosing needs. Conventionaltransdermal drug delivery systems are generally steady state releasedevices providing a-one-size-fits-all regimen, which is not suited forall patient medication regimes.

[0051] According to an embodiment of the present invention, atransdermal patch may be employed with an ultrasonic drug deliverydevice which is ideally wearable by the patient, and/or is aprogrammable device using ultrasound for controlling transdermal and/ortransmucosal flux rates of drugs and other molecules into the body.

[0052] According to an embodiment of the present invention, a method isprovided for non-invasive delivery of molecules, including, but notnecessarily limited to, biologically active molecules, through the skinor mucosal membranes using ultrasound and a transdermal patch.

[0053] According to an embodiment of the present invention, variousultrasound frequencies, intensities, amplitudes and/or phase modulationsmay be applied to control the magnitude of the transdermal flux from thepatch to achieve a therapeutic or nutritional level.

[0054] According to an embodiment of the present invention, the designof the transdermal patch is such that the ultrasound energy istransmitted at a sufficiently high efficiency to permit drug permeationand contains an absorbent material, which holds the drug within thepatch until liberated by ultrasound.

[0055] According to an embodiment of the present invention, a transduceror an array of transducers may be built into the patch. According to anaspect of the present invention, the transducers can be removablyinserted into the patch.

[0056] According to an embodiment of the present invention, ultrasoundmay be combined with iontophoresis, electroporation, depilatories,and/or chemical enhancers such as surfactants to facilitate transdermalpermeation.

[0057] Other advantages and novel features of the invention will beevident from the description which follows, and in part will becomeapparent to those skilled in the art upon examination of the foregoingand/or the following.

[0058]FIG. 1 illustrates one embodiment of this transdermal drug (orother desirable substance) delivery system 100 of this invention.Transdermal drug delivery system 100 comprises an ultrasonic applicator1, placed within functional proximity with a transdermal delivery deviceor patch 2. Patch 2, which contains the substance to be delivered, isplaced in functional proximity to typically contact with the exterior ofthe patient's skin 3 by means of a strap or other suitable stabilizingdevice 4, which strap 4 holds the ultrasonic applicator 1 and patch 2 indesired proximity. Power for the ultrasonic applicator 1 is provided bypower cells or other suitable power supply (not shown) which powersupply is ideally rechargeable, and which may be located within strap 4itself or other convenient location which provides for a fixed portabletransdermal drug delivery system 100. For example, the power supply maybe contained within the ultrasonic applicator device 1 itself orprovided by an external source.

[0059] Reference is hereby made to commonly assigned and copending U.S.patent application Ser. No. 09/939,435, entitled “ULTRASONICALLYENHANCED SUBSTANCE DELIVERY METHOD”, and Ser. No. 09/939,507, entitled“ULTRASONICALLY ENHANCED SUBSTANCE DELIVERY SYSTEM AND DEVICE”, bothfiled on Aug. 24, 2001, the entire disclosures of which are respectivelyhereby incorporated by reference herein.

[0060]FIG. 1 illustrates usage on the arm of the patient, according toan aspect of the present invention. Alternatively, the system may beplaced in contact with some other part of the patient's body asdetermined by the medical personnel or other person administering thedrug or other substance treatment regimen. Such locations may include,but are not necessarily limited to, the patient's chest (as in the caseof nitroglycerin drug delivery, for example), abdomen, neck, back andlegs.

[0061]FIG. 2 illustrates the structure of human skin, showing thevarious structures comprising the skin. According to an aspect of thepresent invention, drug or other substance delivery may be accomplishedby inducing a substance to travel down one or more hair follicles. Insuch an embodiment, the rate of delivery of a large molecule drug orother substance may be increased significantly, when such transmissionis effected at the hair follicle of the skin. This effect may beachieved through the use of ultrasound, altered to a combinationtransmission incorporating both sawtooth and square waveforms. Morespecifically, in this embodiment, the pilosebaceous pores surroundingthe hair follicle may become expanded with this method of substancedelivery and a penetrating drug substance travels down the hair follicleto the hair root, whereupon it is absorbed into the blood stream locatedwithin the vascular network directly under the hair root. This substancepathway enables a greater quantity of the substance to be deliveredultrasonically than can be achieved simply by the use of cavitationeffects upon the surface of the skin leading to microporation of theskin tissue or by simply enabling the drug to pool on the skin andtravel through open skin pores.

[0062] In an embodiment, patch 2 may be subjected to ultrasound for thepurpose of enhancing the penetration of substances, for example,medicinal compounds (drugs) contained within the patch, through tissuesuch as the skin or a mucous or other membrane, and into the patient'sbloodstream. The ultrasonic drug delivery system 100 may be programmedto deliver a medicinal compound to the patient continuously (hereafterreferred to as “sustained release”) or intermittently (hereinafterreferred to as “pulsed release”), whichever may be deemed moreappropriate to a drug maintenance or other treatment regimen for aparticular patient.

[0063]FIG. 5 illustrates one embodiment of an ultrasonic signal whichgenerates the enhanced substance delivery of this invention. The signalof FIG. 5 employs a combination of a sawtooth and a square waveform. Inthis embodiment, the sawtooth wave front effects homogenization of thedrug contained within the patch, and the square waveform which followsdelivers ultrasonic energy to the surface of the skin to effect skintransport.

[0064] As referred to above, FIG. 2 generally illustrates the typicalstructure of human skin. Examples of pathways through the skin into thebloodstream include:

[0065] 1. Breaching the Stratum Corneum.

[0066] 2. Passing a pharmaceutical agent through sweat pores in theskin.

[0067] 3. Passing a pharmaceutical agent through the skin by followingthe pilosebaceous pore to the hair root, and from there into thevascular network located at the base of the hair root.

[0068] In an embodiment of the invention, transdermal drug delivery maybe achieved by utilizing drug pathways associated with the sweat poreand the hair follicle system on the patient's skin. In an embodiment,the ultrasonic frequency, intensity level and waveform dynamics may beadjusted to maximize drug delivery through the hair follicle pathwayprimarily and through the sweat pores in the skin surface secondarily,but not necessarily directly through the stratum corneum. It is believedthat the amount of energy needed for piercing the stratum corneum isexcessive and is also damaging to the fatty tissue. This transportthrough the patch and through the skin hair follicles and sweat pores inthe embodiment of the invention may be enhanced by employing either orboth of the following forces which may be exerted upon the skin surface:

[0069] 1. First, in an embodiment, application of compression or tensileforce to the surface of the skin may constrict the skin to allow thedrug pathways to become more pronounced. Referring to FIG. 1 it can beseen that a strap holds the device to a patient's arm. In addition tosecuring the device to the patient's body, the strap also exerts apressure upon the surface of the skin, constricting the skin. It isbelieved that the constriction offered by a tight strap may affect thepermeability of the skin by: 1) exerting downward pressure upon theskin, perpendicular to the skin surface, 2) stretching the skin suchthat skin pores, such as the sweat pores and/or pilosebaceous pores, aremore readily accessible to a drug; and/or 3) altering the location ofthe fat or other tissue underlying the outer skin layers such thattransdermal delivery is enhanced, thus providing a more substantialpathway for drug delivery than was available by methods of the previousart which employed excessive cavitation energies to the skin surface inhope of breaching the stratum corneum.

[0070] 2. Second, application of force on skin which force is thepressure generated by an ultrasonic signal. It is believed that throughthe use of alternating waveforms the amount of energy transmitted to thesurface of the skin can be minimized, while also providing a pressurewave effect upon the skin, enhancing drug delivery through the hairfollicle and sweat pore system. Referring to FIG. 5, an embodimentemploys a waveform, which alternates from sawtooth to square wave. Theamplitude of and intensity of the wave shaping is believed to aid inboth the homogenization of the drug contained within the transdermalpatch (as seen in FIGS. 3 and 4), helping to miniaturize the beadletsize of the active pharmaceutical substance within the patch, and indrug transport through the skin. It is believed that the short, peakedportion of the ultrasonic waveform in a sawtooth shape helps with drughomogenization, without imparting destructive frequencies and cavitationto the drug substance. Upon conversion to the square waveform theultrasonic transmission acts to massage and open the fatty tissuesurrounding the hair follicles and sweat pores. Drugs permeating fromthe transdermal patch are in monomer form and/or reduced in dropletsize, making them more suitable in dimension to pass through the skin.In an embodiment, the droplet size may be reduced to below approximately50 Angstroms. The square waveform helps to “push” the drug through thepores and alongside the hair follicles, where the drug makes it way tothe hair root, and directly into the bloodstream through the vascularnetwork.

[0071] The parameters of ultrasound that can be changed to improve orcontrol penetration include, but are not necessarily limited to: (1)frequency, (2) intensity, (3) time of exposure and/or (4) ultrasonicwaveform. All of these parameters may be modulated simultaneously in acomplex fashion to increase the effect or efficiency of the ultrasoundas it relates to enhancing the transdermal molecular flux rate eitherinto or out of the human body.

[0072] Since ultrasound is rapidly attenuated in air, a coupling agent,for example one having lowest realizable absorption coefficient that isnon-staining, non-irritating, and slow drying, may be used toefficiently transfer the ultrasonic energy from the ultrasoundtransducer into the skin. When a chemical enhancer fluid oranti-irritant or both are employed, they may function as the couplingagent. For example, glycerin used as an anti-irritant may also functionas a coupling agent. If needed, additional components may be added tothe enhancer fluid to increase the efficiency of ultrasonictransduction. In an aspect of the present invention, resonanceresponsive gels may be used to further enhance the transport of drugsthrough the skin. In addition, maintaining the drug in a sterile andnon-degradable form may be used to increase bioactivity.

[0073] In an embodiment of this invention, transdermal patch 2 mayoperate in conjunction with sonic applicator 1 to achieve ultrasonicallypromoted transdermal delivery of a desired substance. In particular, thecontact between applicator 1 and patch 2 may be adjusted to insureefficient energy transmission. The materials used to construct the patchmay be selected to maintain the intensity and power output of theultrasonic transmission from the transducers through the transdermalpatch. The present invention is particularly suited to deliver largemolecule substances. For example, insulin has a large molecular size,and forms hexamers generally over 50 Angstroms, making it difficult topermeate through the pores of the skin. Insulin molecules tend toagglomerate when stored. Insulin therefore stored within a pocket of thepatch may tend to agglomerate into even larger drug clump sizes,reducing skin transport potential.

[0074] To help alleviate this problem and to keep the drug at a sizesufficiently small enough for skin transport, the waveform of theultrasonic signal delivered by applicator 1 may be altered from time totime, using a sawtooth to a square waveform. FIG. 5 illustrates thealternating waveform concept wherein a sawtooth waveform is moreefficient at homogenization of a drug within the patch, leading toincreased skin transport as the ultrasonic waveform switches to a squarewave shape. Under the sawtooth waveform the short period leads to highenergy, with short duration of pressure amplitude, leading to avibration effect with the targeted pharmaceutical substance. Thisvibration is with low heat and has the effect of mixing or homogenizingthe drug within the patch. Smaller beadlet sizes are made possible bythe sawtooth waveform.

[0075] Referring now to FIGS. 3 and 5, when the sonic transmissionconverts to square waveform induced, more energy is released through thepatch, forcing the homogenized drug through the semi-permeable membrane13 which may be made part of the patch secured to the surface of theskin. There the intensity of the sonic transmission acts upon the poresdirectly alongside the hair follicles as shown in FIG. 2. The squarewaveform enables the pores directly alongside the hair follicle to“open” and become more receptive to drug transport. The deposited drugfollows the hair follicle down through the epidermis to the base root ofthe follicle and is deposited directly into the blood stream within theskin's vascular network. From there the deposited drug is circulatedthrough the body.

[0076] Referring now to FIG. 1, it can be seen a transdermal patch 2, isfirst placed within functional proximity, such as for example, incontact with skin 3 of the patient. In one embodiment of the invention,patch 2 may be affixed to skin 3 by adhesive or other appropriate means.Sonic applicator 1 may be placed in functional proximity to patch 2,such as, for example, in contact with patch 2, such that applicator 1generates an energy signal, for example, an ultrasonic signal whichsignal transverses transdermal patch 2 underneath sonic applicator 1.The substance contained within transdermal patch 2 may be homogenizedinto smaller droplet sizes, which may tend to more readily diffuse thesubstance into and through the skin. The ultrasonic signal may alsoaffect the skin lipids by disrupting and/or disorganizing them to permitthe substance to be delivered. Alternatively, the hair follicle channelsmay serve as substance delivery channels. Regardless of the mechanism,the substance under the influence of ultrasonic signals penetrates thesurface of the skin, travels through the various layers of the skin andfatty tissue and finally is absorbed into the bloodstream and/or tissueof the patient.

[0077]FIG. 3 illustrates an embodiment of the transdermal patch 2 of thepresent invention, referred to here as “patch A”. Transdermal patch 2 isconstructed with a backbone or backing material 10 into which a section,or aperture, has been created incorporating a sonic membrane 11 at thetop of the patch 2. A peel-away film 12 seals patch 2 until use.Peel-away film 12 may be constructed by any suitable material,including, but not limited to, UV-resistant, anti-static polyethylenefilm (50 micrometer thickness) available from Crystal-X Corp., SharonHill, Pa. At the bottom of patch 2 is a semi-permeable member, such as amembrane or film, 13, which comes into functional proximity with theskin, such as within direct contact with the skin when in use. In theinterior of patch 2 an absorbent pad 14 holds the desired drug ormedication compound 15. Ultrasonic signals are transmitted through sonicmembrane 11 and pass through the patch 2 by first traveling through theabsorbent pad 14. Drug or other substance 15, is contained within theabsorbent pad 14 until it is released by the ultrasonic signal, or byother means. The substance then passes through semi-permeable membrane13 and is deposited on or through the surface of the patient's skin.

[0078]FIG. 4 illustrates yet another embodiment of transdermal patch 2of the present invention referred to here as “patch B”. Gasket 16 isplaced between backbone 10 and absorbent pad 14. Gasket 16 may becomposed of any suitable material, such as, for example, syntheticrubber. Gasket 16 forms a reservoir or well over which absorbent pad 14is placed. When pressed upon the skin gasket 16 forms a barrier, whichtends to restrict moisture and air from traveling under the patch andinterfering with the ultrasonic signal intensity. Alternatively, asealant compound, ultrasonic gel or other suitable material may be usedfor or in place of the gasket 16 to provide a sealing action around theborders of patch 2 to provide moisture protection, prevent leakage ofsubstance or the drug from the patch and prevent air from entering underthe patch.

[0079] Referring now to FIG. 6, transducers 18 may be incorporateddirectly within patch 2 or in any other suitable location. In suchconstruction a single transducer may be employed or an array ofultrasonic transducers may be desired.

[0080]FIG. 7 illustrates the underside of patch 2 showing well 17together with semi-permeable membrane 13 over absorbent pad 14.Alternatively or in addition, sealing gasket or compound 16 may beplaced in well 17 of the underside of patch 2.

[0081] Referring now to FIG. 8, according to an embodiment of thepresent invention, a patch, or system, 2 being suitable for beingsecured substantially adjacent to a surface of a subject so as to effectdelivery of at least one substance through the surface and into thesubject is provided. The system 2 may include a backing layer, backingmaterial, backbone, or backbone material, 10 and at least one aperture19 formed in the backing layer 10 for receiving at least one ultrasonictransmission. The system 2 may further include a pad, such as anabsorbent pad, 14 releasably securing the at least one substancesubstantially adjacent to the at least one aperture 19. A sonic member,such as a sonic membrane or film, 11 may be disposed with respect to theat least one aperture 19 so as to communicate the at least onetransmission to the at least one substance so as to effect said deliveryof the at least one substance through the surface of the subject.Optionally, a semi-permeable member, such as a membrane or film, orvalving layer, 13 may be provided.

[0082] In an embodiment of the present invention, ultrasonic signals aretransmitted using a combination frequency of a saw tooth and squarewaveforms as depicted in FIG. 5, which is believed to first homogenizesubstance 15 within the patch 2 and then to effect skin transport oncethe substance 15 has been deposited onto or through the surface of theskin. It may not be necessary for a coupling agent to be used betweenthe skin and the semi-permeable membrane.

[0083] According to an aspect of the invention, the substance 15released from the absorbent pad 14 may pool upon the surface of theskin. This pooled substance may serve to further improve sonictransmission by acting as a sonic coupling agent. According to an aspectof the invention, pooled material may be reabsorbed by the absorbent pad14.

[0084] Referring again to FIGS. 3 and 4, sonic membrane 11 may beconstructed of any suitable resonance compatible material which willenable the sonic transmission emanating from transducer(s) 18 to passthrough sonic membrane 11, and then the absorbent pad 14 and thereafterthrough patch 2 and onto and/or through the patient's skin. Sonicmembrane 11 may be composed of any suitable resonance compatiblematerial which will conduct the ultrasonic transmission without undulydecreasing the effect generated by the transmission of frequency orintensity potential. Suitable resonance compatible materials used forsonic membrane 11 may include, without limitation, polyvinylidenechloride plastic film, such as, for example, the film sold as Saran®,including, but not necessarily limited to, Model Numbers Dow BLF-2014,Dow BLF-2015, Dow BLF-2023, Dow BLF-2050, Dow BLF-2052, Dow BLF-2057,and Dow BLF-2080, available from Dow Chemical Company, Midland, Mich.;and polyester film, for example, Mylar® film, including, but notnecessarily limited to, Model Numbers M30, M33, M34, D887, MC2, andSBL-300, available from DuPont Teijin Films Div., Wilmington, Del.Polyvinylidene chloride film has been found to be effective as a sonicmembrane material, however many other materials may also provide asimilar function. The materials of patch 2 may be chosen or fabricatedfor resonance compatibility with a desired frequency and intensity ofultrasound to be used for a particular substances or drug's skintransport dynamics.

[0085] In an embodiment of the invention, sonic membrane 11 may beaffixed to absorbent pad 14 with a suitable resonance compatiblematerial, including, but not limited to, a flat layer of polymer epoxy.One suitable material is a polyurethane material, such as Uralite®,available from H. B. Fuller Company, St. Paul, Minn.

[0086] Absorbent pad 14 may be composed of any suitable material, suchas a non-woven cellulose fiber or any similarly acting material whichwill absorb or otherwise hold drug 15 during storage within patch 2, butalso release drug 15 upon transmission of the ultrasonic signal throughpatch 2. Other possible materials may be used, including, but notlimited to, natural sponges, fused silica, and various woven andnon-woven materials. Examples of suitable materials include, withoutlimitation, CoTran 9729, a non-woven polypropylene material availablefrom 3M, St. Paul, Minn.; Pop-Up Compressed Sponge (comprising 76%cellulose, 7.7% polyol, and 15.5% NaCl), available from Clipper Mill,San Francisco, Calif.; Microdon Web, Model Number M-261420025, anon-woven polyester fiber blend, available from 3M, St. Paul, Minn.;Vizorb #3010, a cellulose pad comprising wood pulp and ethylene vinylacetate based synthetic latex, available from Buckeye AbsorbentProducts, Memphis, Tenn.; and Vicell # 6009, a cellulose pad comprisingwood pulp and ethylene vinyl acetate based synthetic latex, availablefrom Buckeye Absorbent Products, Memphis, Tenn.

[0087] A semi-permeable membrane 13 may be placed at the bottom of patch2, such that it comes into direct contact with the patient's skin. Sucha semi-permeable membrane 13 may function like a valve, enabling drug 15released from absorbent pad 14 to pass through semi-permeable membrane13 only with the active generation of ultrasound. When no ultrasonicsignal is present, semi-permeable membrane 13 prevents a significantamount of the drug from permeating the membrane onto or through thesurface of the patient's skin. The valving action of semi-permeablemembrane 13 may provide a means of controlling the dose delivered to thepatient. It is believed that a sonicated skin section may remainpermeable to a delivered substance such as a drug, for some amount oftime after the ultrasonic signal has been terminated. If drug 15 were toreach the skin in this case, the skin might continue to absorb the drugeven after the cessation of the ultrasonic signal. Assuming that asteady rate of delivery can be achieved with an active ultrasonicsignal, the delivery of the proper dose would be proportional to thenumber of seconds or minutes that an active ultrasonic signal waspresent upon the skin surface. In such a manner the delivered drug doselevels would be comparable to the timing of active ultrasonic signal.

[0088] If continued skin permeation follows the cessation of activeultrasonic signal, it may be difficult to ascertain the exact amount ofdose actually delivered to the patient. Hence a valving patch, whicheffectively shuts down drug delivery when the ultrasonic signal isterminated, may be provided. A sonically reactive semi-permeablemembrane 13 may be used at the base of patch 2 in order to insure thatpatch 2 delivers the drug only with the presence of a ultrasonic signal,timed to deliver the proper dose by a timing circuit in sonic applicatordevice 1 depicted in FIG. 1, for example.

[0089] Suitable elastomeric materials that change properties whenexposed to changes in pressure and/or temperature may be used toconstruct semi-permeable membrane 13. In an embodiment of the invention,any suitable material, including, but not limited to, natural sponge andperforated polymer films may be used as a semi-permeable membrane 13.Ultrasonic signals are believed to generate a cavitation effect inpolymer films, expanding the diameter of the perforations of the film,thereby enabling the film to become more permeable. When an ultrasonicsignal is not present, the elasticity of the film may enable it toreturn to its original structure and reduce the diameter of anyperforation, thereby blocking a large molecule substance containedwithin patch 2 from further transport from patch 2 to the skin.

[0090] According to an embodiment of the invention, semi-permeablemembrane 13 may be constructed of any suitable semi-permeable materialthat, in the absence of an ultrasonic signal, does not permit diffusionof a solution containing a drug across the membrane, but permitsdiffusion of a drug solution through the membrane upon being subjectedto an ultrasonic signal.

[0091] According to an embodiment of the invention, semi-permeablemembrane 13 may be constructed of any suitable thermoplastic material.Such a material may change properties upon being subjected to anincrease in temperature as a result of a ultrasonic vibrations, andreturn to its original state upon cessation of the ultrasonic signal.According to an embodiment of the invention, semi-permeable membrane 13may be constructed of any suitable thermoplastic elastomer that changesits permeability properties upon being subjected to an ultrasonicsignal, allowing movement of the drug across the membrane, andsubstantially returns to its original permeability state upon cessationof the ultrasonic signal.

[0092] According to an embodiment of the invention, semi-permeablemembrane 13 may be constructed of any suitable ionomer (ion-containingpolymer), including, but not necessarily limited to, those ionomers thatfunction as thermoplastic elastomers. According to an embodiment of theinvention, suitable ionomers include, but are not necessarily limitedto, ethylene-co-methacrylic acid copolymers (such as, for example, thefilm sold as Surlyn®, available from DuPont, Wilmington, Del.).

[0093] As the transdermal patch 2 releases the contents of drug 15,patch 2 may be replaced by a new patch 2. New patch 2 may then beemployed for another drug delivery period. Alternatively, additionalquantities of a substance or pharmaceutical agent may be inserted intopatch 2 by appropriate means to effectively “re-load” the patch. In anembodiment, when patch 2 is replaced, it may be uncoupled fromtransducer assembly 18 or other source of the ultrasonic signal.

[0094] According to an embodiment of the invention, patch 2 is attachedto one or more transducers 18 by a sonic adhesive or coupling agent. Thesonic adhesive may be any suitable material, including, but not limitedto, a mineral oil. An example of a suitable mineral oil is Draecol 9,available form Eastern Chemical, Philadelphia, Pa.

[0095] Alternatively, a fold at the top of transdermal patch 2 may beused to enable the transducer(s) 18 to slide into the topmost section ofthe patch, for example. Transducers 18 may be built directly into thestructure of the patch as shown in FIG. 6.

[0096] Backbone 10 of patch 2 may be made from any suitable material,including, but not limited to, polyolefin film or polyvinyl chloride. Anexample of suitable materials are Polyvinyl Chloride Foam Tape 9772-Lavailable from 3M, St. Paul, Minn. and Model Number 3M 9773 Foam Tape, apolyolefin foam tape with adhesive backing, available from 3M, St. Paul,Minn. Backbone material 10 may also possess adhesives, such as, forexample, the pressure-sensitive acrylate adhesive used on 3M 9772-LFoamTape, available from 3M, St. Paul, Minn., which will enable the patch 2to adhere to the surface of the patient's skin.

[0097] According to an embodiment of the invention, backing member 10,comprising Model Number 9772-L Foam Tape (3M, St. Paul, Minn.) includesat least one aperture that is covered by sonic membrane 11 comprisingSaran® film, Model Number Dow BLF-2014 (Dow chemical Co., Midland,Mich.) or Mylar® film, Model Number M34, DuPont Teijin Films,Wilmington, Del. At least one absorbent pad 14 comprising cellulosematerial (Model Number Vicell® # 6009, Buckeye Absorbent Products,Memphis, Tenn.) may be placed such that ultrasonic energy is transmittedthrough sonic membrane 11 to absorbent pad 14. In the presence of anultrasonic signal, insulin solution (Humulin®R, Eli Lilly, Indianapolis,Ind.) contained on or within absorbent pad 14 may move throughsemi-permeable membrane 13, comprising Surlyn® film (DuPont, Wilmington,Del.), and be delivered to a subject. Peel-away film 12 comprisingUV-resistant anti-static polyethylene film (50 micrometer thickness)(Crystal-X Corp., Sharon Hill, Pa.) may be utilized.

[0098] According to an embodiment of the invention, patch 2 may enableultrasonic signal transmission completely therethrough. Therefore, itmay be desirable to minimize attenuation of the ultrasonic signal as ittravels through the materials in patch 2. Of particular concern arepockets containing, for example, air, gas, or moisture located withinthe absorbent materials used in patch 2, which may act to later thefrequency and/or intensity of the transmitted ultrasonic signal. Tofacilitate an improved ultrasonic transmission through the patch,absorbent material may be treated using vacuum freeze drying to removetrapped air from within the absorbent material. In this method thematerial is frozen by freeze drying and then vacuum dried. One effect offreeze-drying is the

[0099] reduction of the amount of trapped air within the weave of theabsorbent material, thus making the absorbent material more resonancecompatible with the frequency and intensity of the ultrasonictransmission and improving its attenuation properties.

[0100] According to an embodiment of the invention, the absorbent padmaterial may be soaked in an aqueous solution of 0.9% NaCl prior to thefreeze-drying treatment. The pre-treatment with the saline solutionprovides that a residue of NaCl remains in the absorbent material. Thesalt residue acts as a humectant, attracting water and thus maintainingsome moisture within the absorbent pad. Preventing the absorbent padfrom drying out allows the drug stored in the pad to remain in solution,preventing loss of moisture that may cause the drug solution to becomeincreasingly concentrated. Concentration of the drug solution may beavoided, as it may lead to aggregation or precipitation of the activedrug from the solution, impeding drug transport.

[0101] Suitable material for an absorbent pad may possess one or more ofthe following characteristics:

[0102] 1) High absorbency for the selected drug presented in an emulsionor solution form.

[0103] 2) The absorbent material is inert with respect to the selectdrug, or its excipient or preservatives used in the solution form of thedrug, over a protracted period of storage time.

[0104] 3) The absorbent material is resistant to degradation underexposure to ultrasound, and to releasing contaminants into the storeddrug.

[0105] 4) The absorbent material is essentially free of metallic,organic or inorganic contaminants.

[0106] 5) The absorbent material is non-irritating to human skin andremains stable upon interaction with human sweat.

[0107] 6) The absorbent material remains stable in a stored form for oneyear or more and is resistant to degradation with time when soaked withthe drug.

[0108] 7) The absorbent material may be composed of natural or syntheticmaterials.

[0109] According to an embodiment of the invention, the absorbentmaterial is superabsorbent, defined as a material capable of absorbingabout fourteen (14) or more times its weight in liquid. Such asuperabsorbent material provides the pad with the capacity to store thedrug in a dilute solution or suspension. This may be of particularimportance for polypeptides such as insulin, which is believed to formmultimeric structures when concentrated in solution. Preventing theabsorbent pad from drying out, and thus maintaining insulin in dilutesolution, maintains the insulin in monomeric form, which is most easilytransported out of the patch and through the skin.

[0110] According to an embodiment of the invention, the absorbentmaterial contains functional groups capable of cross-linking with thedrug Such cross-linking may act to stabilize the drug for storage whilein patch 2. When an ultrasonic signal is applied through patch 2, uponreaching the absorbent material the ultrasonic signal may causedisruption of the cross-linking such that the drug is released from theabsorbent material and is free to be delivered to the subject.

[0111] According to an embodiment of the invention, the absorbentmaterial may be formed from material that contains moderate amount ofcrosslinking points, such that the absorbent material formscross-linkages with the drug, but does not form cross-linkages thatdisrupt the native structure of the drug, and such that, upon exposureto ultrasonic signals, releases the cross-linking such that the drug isno longer bound to absorbent pad 14 and is free to be delivered to thetissue of the subject.

[0112] According to an embodiment of the invention, the absorbentmaterial and the drug are cross-linked through hydrogen bonding.According to an embodiment of the invention, the absorbent materialcontains functional groups able to form hydrogen bonds with functionalgroups of a polypeptide drug, such as, for example, insulin. In thiscase, the hydrogen bonding acts to stabilize the structure of the drug.Upon exposure to an ultrasonic signals, the hydrogen bonding thatcross-links the drug to the absorbent material is disrupted withoutbreaking the hydrogen bonds that form the native secondary structure orother aspects of the structure of the polypeptide.

[0113] Table 1 lists at least some of the materials, which may beutilized in the construction of absorbent pad 14: TABLE 1 EXAMPLE OFMATERIALS SUITABLE FOR ABSORBENT PAD 14 Cellulose Fiber Pad CootonNatural Sponge Woven Cloth Fabrics Polyurethane foams PolyisocyanateFoams Non-Woven Cloths Fused Silica Starch Corn Meal Wood Pulp fibersCollagen Pads Poly methyl methacrylate Polyvinyl alcohol Poly vinylpyrrolidine Poly acrylic acid Poly (2-hydroxy ethyl methacrylatePolyacrylamide Poly ethylene glycol Polylactides(PLA)Polyglycolides(PGA) Poly(lactide-Co-glycolides) Polycarbonate Chitosan

[0114] Any other natural or synthetic materials, which may act to absorbthe drug compound and be able to release the drug upon ultrasonicexcitation.

[0115] According to an embodiment of the invention, the absorbentcompound may be a non-woven material having a moderate amount offunctional groups available for cross-linking. When the absorbentmaterial contacts a drug, the functional groups of the absorbentmaterial form cross-links with the drug such that the structure of thedrug is stabilized in the absence of an ultrasonic signal. When anultrasonic signal is transmitted through the patch to the absorbentmaterial, the cross-linking may be disrupted such that the drug isreleased from the absorbent material without contamination of ordisruption of the native structure of the drug.

[0116] According to an embodiment of the invention, the absorbentmaterial is treated by freezing, followed by vacuum drying. Suchfreeze-drying of the absorbent material acts to reduce the amount ofcontaminants such as air or moisture that may be trapped in theabsorbent material. Such contaminants may react with functional groupsof the absorbent material, thus preventing these functional groups fromforming cross-links with the drug. Upon freeze-drying, such contaminantsare removed, thus freeing the cross-linking sites of the absorbentmaterial such that the sites are free to form cross-linkages with thesubstance to be delivered. In addition, the freeze-drying may removecontaminants that otherwise might react with or contaminate the drug.

[0117] According to an embodiment of the invention, the absorbentmaterial may be capable of retaining the drug in the absence of anultrasonic signal, of releasing the drug upon excitation by anultrasonic signal, and has absorbent properties such that any excessdrug left upon the skin surface after the ultrasonic signal isterminated is reabsorbed into the absorbent pad and is not releaseduntil another ultrasonic signal is transmitted to the absorbentmaterial. This function of the absorbent material enables the accuratecontrol of the delivered drug dose by parameters of the ultrasonicsignal and may eliminate the need for a semi-permeable “valving”membrane to control the dose. According to an aspect of the invention, amaterial having a capacity to absorb from between about one and aboutfour times its weight in drug solution may provide the appropriateabsorption/release/reabsorption properties that would enable controlleddosage release via ultrasound. The rate of absorption may be adjusted byutilizing different types and combinations of fibers to produce theabsorbent material. For example, cellulose material may be produced fromfibers originating from various types of wood (for example, “hard”versus “soft” woods) having different absorbent properties.

[0118] In accordance with an embodiment of the invention, as ultrasonicsignals are transmitted through the patch 2 the signal massages thepores directly surrounding the hair follicle, increasing thepermeability of the pore. Ultrasonic signals enhance the transport ofdrug 15 stored within absorbent pad 14 within patch 2, acrosssemi-permeable membrane 13 and deposits drug 15 onto the skin surface,where drug 15 is absorbed into the body by traveling down the hairfollicle to the hair root and into the vascular network.

[0119] In accordance with an embodiment of the invention, the ultrasonictransmission may have a frequency in the range of about 20 kHz to about10 MHz. The intensity of said ultrasonic transmission may be in therange of about 0.01 W/cm² to about 5.0 W/cm². Changes in frequency andintensity levels may require alteration of the materials used in theconstruction of transdermal patch 2 to accommodate optimum performancein both drug delivery and in the valving function effected bysemi-permeable film 13.

[0120] In accordance with an embodiment of the invention, while awaveform converting from sawtooth to square has been described, atraditional sinusoidal waveform may also be effective as a drug deliverywaveform for the ultrasonic transmission.

[0121] Apparatus and methods according to the present invention areuseful for delivering a wide variety of substances to a patient. Asdescribed in greater detail herein, the substances may be delivered, forexample, transdermally, transcutaneously, intralumenally, and withinsolid tissue sites, where in all cases absorption of the substance or apharmacologically active portion thereof into the underlying orsurrounding tissue is phonophoretically enhanced by the application ofultrasonic or sonic energy. The substance may take any suitable form,including, but not limited to, liquids, gels, porous reservoirs,inserts, or the like, and the substance or pharmacologically activeportion thereof may, for example, treat or alleviate an existingcondition or prophylactically prevent or inhibit another condition ofthe patient. The effect of the substance may be local, such as providingfor anti-tumor treatment, or may be systemic. Suitable medicamentsinclude, but are not limited to, broad classes of compounds normallydelivered through the skin and other body surfaces or into solidtissues.

[0122] In general, such medication may include or incorporate substancesincluding, but not limited to, the following: anti-infectives such asantibiotics and antiviral agents; analgesics and analgesic combinations;anorexics; antihelminthics; antiarthritics; antiasthmatic agents;anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals;antihistamines; antiinflammatory agents; antimigraine preparations;antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics;antipsychotics; antipyretics; antispasmodics; anticholinergics;sympathomimatics; xanthine derivatives; cardiovascular preparationsincluding, but not limited to, potassium and calcium channel blockers,beta-blockers, and antiarrhythmics; antihypertensives; diuretics;vasodilators including general coronary, peripheral and cerebral;central nervous system stimulants; cough and cold preparations,including decongestants; hormones, including, but not limited tosteroids, including, without limitation, estradiol, and corticosteroids;hypnotics; immunosuppressives; muscle relaxants; parasympatholytics;psychostimulants; sedatives; and tranquilizers. By the method of thepresent invention, ionized and nonionized drugs may be delivered, as candrugs of high or low molecular weight.

[0123] Proteinaceous and polypeptide drugs represent one class of drugssuitable for use in conjunction with the presently disclosed invention.Such drugs cannot generally be administered orally in that they areoften destroyed in the gastrointestinal tract or metabolized in theliver. Further, due to the high molecular weight of most polypeptidedrugs, conventional transdermal delivery systems are not generallyeffective.

[0124] Common examples of pharmaceutical or nutritional compounds whichmay be contained within transdermal patch 2 of this invention include,but are not limited to: acetaminophen, antibiotics, aspirin,corticosterone, erythromycin, ibuprofen, insulin, nitroglycerin,nicotine, steroids, including without limitation, progesterones,estrogens, for example, estradiol, and vitamins. Suitable forms ofinsulin include, but are not necessarily limited to, Humulin®R andHumulog®, both available from Eli Lilly and Company, Indianapolis, Ind.Any other substance, including, but not limited to, pharmaceuticaland/or nutritional compounds used for nutraceutical, medicinal orpharmaceutical purposes, and any combinations thereof, may also beutilized. It may also desirable to use the method of the invention inconjunction with drugs to which the permeability of the skin isrelatively low, or which give rise to a long lag-time. Application ofultrasonic signals as described herein has been found to significantlyreduce the lag-time involved with the transdermal administration of mostdrugs.

[0125] The use of ultrasonic signals coupled with iontophoresis, theapplication of electric currents applied to the skin, has been attemptedin various forms of drug delivery. In some instances ultrasonic signalswas used together with iontophoresis while in others ultrasound was apre-treatment to the application of iontophoresis. Applicants have notedthe method of iontophoresis in combination with the apparatus of thisinvention can be used to enhance molecular transport through the skin.

[0126] The use of chemical substances, often referred to as chemicalenhancers, can enhance drug transport in this invention as well.

[0127] According to an embodiment of the invention, a safety feature,which indicates that the patch is empty or has been used, may beincorporated. The use of a ultrasonic contrast agent or color forminglabel within the patch which will turn color, for example from green tored, when exposed to ultrasound, may be provided as a means ofindicating that the patch has been used.

[0128] According to an embodiment of the present invention, transdermalpatch 2 may be fitted with a bio-sensor which detects the glucose levelof the patient, either through invasive or non-invasive means, with thedata from the sensor being used to control the application of medicationfrom the patch and the timing of the drug delivery.

[0129] According to an embodiment of the invention, transdermal patch 2may be fitted with a bio-sensor, which would detect the amount ofmedication actually delivered to the patient. Such a sensor may measurethe electrical resistance of the patient's skin. Delivery of a drugthrough the skin causes a readable change in the electrical conductivityof the skin tissue surrounding the transport site. The data from such abio-sensor could be used to record the actual quantity of the drugdelivered from the patch to the patient.

[0130] Referring now to FIG. 9, a transdermal delivery device orassembly 300 according to an aspect of the present invention isillustrated therein. Such a delivery device may include a transducercoupler 201, which includes a transducer housing 202 into the interiorof which at least one ultrasonic transducer 18 or an array oftransducers 18 may be placed. According to an aspect of the invention,the array of transducers 18 may be a 2×2 array. The delivery device mayfurther include a cap unit or patch cap 210 which houses an absorbentpad 14 containing at least one substance to be delivered. A sonicmembrane 11 may be made part of the cap unit 210, or affixed to the capunit 210, such that it covers the absorbent pad 14 on a side which isplaced in contact with the transducer coupler 201. According to anaspect of the invention, the sonic membrane 11 may be constructed ofpolyvinylidene chloride plastic film, such as, for example, the filmsold as Saran®, including, but not necessarily limited to, Model NumberDow BLF-2014, available from Dow Chemical company, Midland, Mich.According to an aspect of the invention, the sonic membrane 11 may havea diameter of about 4.0 cm and a thickness of about 50 μm. According toan aspect of the invention, the sonic membrane 11 may be constructed ofpolyester film, for example, Mylar® film, including, but not necessarilylimited to, Model Number M34, available from DuPont Teijin Films Div.,Wilmington, Del. According to an aspect of the invention, the sonicmembrane may have the following approximate dimensions: 4.0 cmdiameter×13 μm thickness. A peel-away film 12 may be made part of thecap unit 210 such that prior to the removal thereof, it covers a side ofthe absorbent pad 14 that is to be placed against a substance deliverytarget, such as the skin of a subject. Upon removal of the peel-awayfilm 12, absorbent pad 14 containing at least one substance may beexposed so as to be secured adjacent to a substance delivery target.

[0131] According to an aspect of the invention, the cap unit 210 mayoptionally include a semi-permeable membrane 13 on the underside of thecap 210, such that the semi-permeable membrane 13 comes into functionalproximity with the surface of a subject. The semi-permeable membrane 13may be constructed of any suitable material, including, but notnecessarily limited to, ethylene-co-methacrylic acid copolymers (suchas, for example, the film sold as Surlyn®, available from DuPont,Wilmington, Del.). According to an aspect of the invention, thesemi-permeable membrane 13 may have the following approximatedimensions: 4.0 cm width×4.0 cm length×50 μm thickness.

[0132] The transdermal delivery device may be constructed such that thecap unit 210 may snap or be screw coupled onto the transducer coupler201 to produce a transdermal delivery device or assembly. The cap unit210 and transducer coupler 201 may be joined together using threadedcoupling, male-female connector grooves, a bayonet catch-type system orother connection coupling system or device (collectively referred toherein as a screw coupling). The screw coupling may engage transducercoupler 201 and cap unit 210 by spinning or turning transducer coupler201 and cap unit 210 so that coupler 201 and cap unit 210 substantiallyengage. An example of a screw coupling, which may have a single spin orturn, is an arrangement like that of a child-proof cap commonly used inpharmaceutical packaging.

[0133] An electrical lead or cable 204 may be used to connect thetransducer(s) 18 with a power source and/or a control unit 400 (FIG.32G) and may lead away from the transducer coupler 201.

[0134] A strap 250 may be used to secure the transdermal delivery device300 to a body of a subject. Pressure produced by the strap 250connection to the subject may establish an interface between theabsorbent pad 14 and the surface of the subject. The pressure producedby the strap 250 connection to the subject may be used to establish asonic connection or interface between the absorbent pad 14 and thesurface of the subject. The pressure produced by the strap connection250 may establish an interface between the absorbent pad 14 and thesurface of the subject that substantially prevents the leakage of asubstance from under the cap 210 and also substantially preventscontamination of the substance being delivered to the surface of thesubject.

[0135] According to an aspect of the invention, the cap unit 210 mayinclude interior threading, and may be screw coupled onto the transducercoupler 210, which may have exterior threading. Pressure induced by thescrewing of the cap unit 210 onto the transducer coupler 201 mayestablish a sonic connection or interface between the transducer coupler201 and the sonic membrane 11 of the cap unit 210. The pressure inducedby the screwing of the cap unit 210 onto the transducer coupler 201 mayestablish a sonic connection or interface between the sonic membrane 11and the absorbent pad 14.

[0136] Alternatively, according to an aspect of the invention, thetransducer coupler 201 may screw coupled onto the cap unit 210analogously.

[0137] Referring now to FIG. 10, a transducer coupler 201 suitable foruse with the present invention is shown therein. This transducer coupler201 may include a housing 202 having at least one transducer capconnector groove 203. The transducer coupler may further include a sonicface plate 205 designed to form a sonic interface with a cap unit 210(FIG. 9). According to an aspect of the invention, the transducercoupler 201 may be about 4.0 cm in diameter and about 1.0 cm thick, andproduced by Sonic Systems, Inc., Newtown, Pa. The housing 202 may beconstructed of any suitable material. According to an aspect of theinvention, the housing 202 may be constructed of a plastic component,such as, for example, the epoxy sold as Eccobond® 45LV and catalyst15LV, available from Emerson & Cuming, Billerca, Mass. The sonic faceplate 205 may be composed of any sonically compatible material, such as,for example, an approximately 4.0 cm diameter×1.0 mm thick stainlesssteel plate, available from Sonic Systems, Inc., Newtown, Pa.

[0138] Referring now to FIG. 11, a cap unit 210 suitable for use withthe transducer coupler 201 of FIG. 10 is shown therein. The cap unit 210may be constructed of plastic or any sonically compatible material. Capunit 210 may include an absorbent pad 14 (FIG. 9) which contains atleast one substance to be delivered. According to an aspect of theinvention, the absorbent pad 14 may be constructed of a cellulose pad,including wood pulp with ethylene vinyl acetate-based synthetic latex,such as Vicell # 6009, available from Buckeye Absorbent Products,Memphis, Tenn. According to an aspect of the invention, the absorbentpad 14 may be approximately 4.0 cm in diameter and 0.92 mm thick. Thecap unit 210 may further include an adhesive, or sealing ring 213suitable for contacting the skin of a subject and forming a sealsubstantially preventing the entry of air or contaminants under or intothe device and the leakage or contamination of a substance depositedupon the skin of a subject by the transdermal delivery device. Accordingto one aspect of the invention, the adhesive ring 213 may be constructedof Foam Tape Model No. 3M 9772-L, polyvinyl chloride with adhesivebacking, available from 3M Co., St. Paul, Minn. According to an aspectof the invention, the adhesive ring 213 may be constructed of Model No.3M 9773 Foam Tape, polyolefin film with adhesive backing. According toan aspect of the invention, the adhesive ring 213 may have the followingapproximate dimensions: inner aperture: 3.75 cm diameter, ringdimensions: 0.25 cm×1.0 mm thick.

[0139] The cap unit 210 may have a textured surface 212 on an outersurface of the cap 210 to improve a user's ability to grip and turn thecap 210. According to an aspect of the invention, the cap unit 210 maybe about 4.0 cm in diameter×about 0.75 cm thick, as provided byDefinitive Design Co., Langhorne, Pa. According to one aspect of theinvention, the cap unit 210 may be disposable, such that after thesubstance is dispensed from the cap 210 the cap may be discarded andreplaced with a fresh cap unit 210. Alternatively, the pad 14 may beadapted to be replaced without requiring a new cap unit 210. Either way,additional substance to be delivered may be provided without replacingthe transducer coupler 201. Of course, the device 300 (FIG. 9) could bedesigned such that the transducer coupler 201 (FIG. 10) may be replacedperiodically or the entire assembly 300 may be designed as a singlenon-reusable device.

[0140] Referring now to FIG. 12, the cap unit 210 may be constructed ofan outer snap ring 230 and an inner snap ring 220 nested inside of theouter snap ring 230. According to an aspect of the invention, the innersnap ring 220 may substantially secure the absorbent pad 14 in place.Referring now also to FIGS. 13 and 14, the inner snap ring 220 mayinclude at least one inner connector tab or bayonet 222 and at least oneouter connector tab 221. The outer snap ring 230 may include at leastone connector groove 211 into which the outer connector tab 221 of theinner snap ring 220 may be inserted so as to screw couple the inner snapring 220 to the outer snap ring 230. The inner connector tab 222 may befitted into the transducer cap connector groove 203 (FIG. 10) to allow atight connection when the cap unit 210 is screw coupled with thetransducer coupler 201. According to an aspect of the invention, theconnection between the cap unit 210 and the transducer coupler 201 mayform a sonic connection between the absorbent pad 14 and the transducercoupler 201. In such a configuration the absorbent pad 14 may be securedadjacent or substantially adjacent to the transducer coupler 201.

[0141] Referring now to FIGS. 15 and 16, a transdermal delivery deviceor assembly 300 according to an aspect of the present invention isillustrated therein. Such a delivery device may include a transducercoupler 201, which includes a transducer housing 202 into the interiorof which at least one ultrasonic transducer 18 (not shown) or an arrayof transducers 18 may be placed. According to an aspect of theinvention, the array of transducers may be a 2×2 array. The deliverydevice may further include a cap unit or patch cap 210 which houses anabsorbent pad 14 (shown in FIG. 32A) containing at least one substanceto be delivered. A sonic membrane 11 (not shown) may be made part of thecap unit 210, or affixed to the cap unit 210, such that it covers theabsorbent pad 14 on a side which is placed in contact with thetransducer coupler 201. According to an aspect of the invention, thesonic membrane 11 may be constructed of polyvinylidene chloride plasticfilm, such as, for example, the film sold as Saran®, including, but notnecessarily limited to, Model Number Dow BLF-2014, available from DowChemical company, Midland, Mich. According to an aspect of theinvention, the sonic membrane 11 may have a diameter of about 4.0 cm anda thickness of about 50 μm. According to an aspect of the invention, thesonic membrane 11 may be constructed of polyester film, for example,Mylar® film, including, but not necessarily limited to, Model NumberM34, available from DuPont Teijin Films Div., Wilmington, Del. Accordingto an aspect of the invention, the sonic membrane may have the followingapproximate dimensions: 4.0 cm diameter×13 μm thickness. A peel-awayfilm 12 (not shown) may be made part of the cap unit 210 such that priorto the removal thereof, it covers a side of the absorbent pad 14 that isto be placed against a substance delivery target, such as the skin of asubject. Upon removal of the peel-away film 12, absorbent pad 14containing at least one substance may be exposed so as to be securedadjacent to a substance delivery target.

[0142] According to an aspect of the invention, the cap unit 210 mayoptionally include a semi-permeable membrane 13 (not shown) on theunderside of the cap 210, such that the semi-permeable membrane 13 comesinto functional proximity with the surface of a subject. Thesemi-permeable membrane 13 may be constructed of any suitable material,including, but not necessarily limited to, ethylene-co-methacrylic acidcopolymers (such as, for example, the film sold as Surlyn®, availablefrom DuPont, Wilmington, Del.). According to an aspect of the invention,the semi-permeable membrane 13 may have the following approximatedimensions: 4.0 cm width×4.0 cm length×50 μm thickness.

[0143] The transdermal delivery device may be constructed such that thecap unit 210 and the transducer coupler 201 may be press-fit or snappedtogether to form a transdermal delivery device or assembly 300. The capunit 210 and transducer coupler 201 may be joined together using a pressfit or snap connection or other suitable connection coupling system ordevice.

[0144] An electrical lead or cable 204 may be used to connect thetransducer(s) 18 (not shown) with a power source and/or a control unit(400) (shown in FIG. 32G) and may lead away from the transducer coupler201.

[0145] A strap 250 (not shown) may be used to secure the transdermaldelivery device 300 to a body of a subject (shown in FIGS. 32E and 32F).Pressure produced by the strap 250 connection to the subject mayestablish a functional interface between the absorbent pad 14 (FIG. 32A)and the surface of the subject. The pressure produced by the strap 250connection to the subject may be used to establish a sonic connection orinterface between the absorbent pad 14 and the surface of the subject.The pressure produced by the strap 250 connection may establish aninterface between the absorbent pad 14 and the surface of the subjectthat substantially prevents the leakage of a substance from under thecap 210 and also substantially prevents contamination of the substancebeing delivered to the surface of the subject.

[0146] Pressure induced by the snapping or pressing of the cap unit 210onto the transducer coupler 201 may establish a sonic connection orinterface between the transducer coupler 201 and the sonic membrane 11of the cap unit 210. The pressure induced by the snapping or pressing ofthe cap unit 210 onto the transducer coupler 201 may establish a sonicconnection or interface between the sonic membrane 11 and the absorbentpad 14.

[0147] Alternatively, according to an aspect of the invention, thetransducer coupler 201 may be snapped or press fit onto the cap unit 210analogously.

[0148] Referring now to FIGS. 17 and 18, a transducer coupler 201suitable for use with the present invention is shown therein. Thistransducer coupler 201 may further include a housing 202 having at leastone transducer cap connector groove 203. The transducer coupler mayfurther include a sonic face plate 205 designed to form a sonicinterface with a cap unit 210 (FIG. 15). According to an aspect of theinvention, the transducer coupler 201 may be about 4.0 cm in diameterand about 1.0 cm thick, and produced by Sonic Systems, Inc., Newtown,Pa. The housing 202 may be constructed of any suitable material.According to an aspect of the invention, the housing 202 may beconstructed of a plastic component, such as, for example, the epoxy soldas Eccobond® 45LV and catalyst 15LV, available from Emerson & Cuming,Billerca, Mass. The sonic face plate 205 may be composed of anysonically compatible material, such as, for example, an approximately4.0 cm diameter×1.0 mm thick stainless steel plate, available from SonicSystems, Inc., Newtown, Pa.

[0149] Referring now to FIGS. 19 through 22, the cap unit 210 (shown inFIGS. 32A and 32B) may be constructed of an outer snap ring 230 (shownin FIGS. 21 and 22) and an inner snap ring 220 (shown in FIGS. 19 and20) secured substantially within the outer snap ring 230 (as shown inFIG. 32C). According to an aspect of the invention, when the inner snapring 220 is secured substantially within the outer snap ring 230, theinner snap ring 220 may substantially secure the absorbent pad 14 inplace (shown in FIG. 32A).

[0150] The cap unit 210 may be constructed of any suitable material.According to an aspect of the invention, the cap unit 210 may be about4.0 cm in diameter×about 0.75 cm thick, as provided by Definitive DesignCo., Langhorne, Pa. According to one aspect of the invention, the capunit 210 may be disposable, such that after the substance is dispensedfrom the cap unit 210 the cap unit 210 may be discarded and replacedwith a fresh cap unit 210. Alternatively, the pad 14 may be adapted tobe replaced without requiring a new cap unit 210. Either way, additionalsubstance to be delivered may be provided without replacing thetransducer coupler 201. Of course, the device 300 (FIG. 15) could bedesigned such that the transducer coupler 201 (FIG. 17) may be replacedperiodically or the entire assembly 300 may be designed as a singlenon-reusable device.

[0151] Cap unit 210 may include an absorbent pad 14 (FIG. 32A) whichcontains at least one substance to be delivered. According to an aspectof the invention, the absorbent pad 14 may constructed of a cellulosepad, including wood pulp with ethylene vinyl acetate-based syntheticlatex, such as Vicell # 6009, available from Buckeye Absorbent Products,Memphis, Tenn. According to an aspect of the invention, the absorbentpad 14 may be approximately 4.0 cm in diameter and 0.92 mm thick. Thecap unit 210 may further include an adhesive, or sealing ring 213 (notshown) suitable for contacting the skin of a subject and forming a sealsubstantially preventing the entry of air or contaminants under or intothe device and the leakage or contamination of a substance depositedupon the skin of a subject by the transdermal delivery device. Accordingto one aspect of the invention, the adhesive ring 213 may be constructedof Foam Tape Model No. 3M 9772-L, polyvinyl chloride with adhesivebacking, available from 3M Co., St. Paul, Minn. According to an aspectof the invention, the adhesive ring 213 may be constructed of Model No.3M 9773 Foam Tape, polyolefin film with adhesive backing. According toan aspect of the invention, the adhesive ring 213 may have the followingapproximate dimensions: inner aperture: 3.75 cm diameter, ringdimensions: 0.25 cm×1.0 mm thick.

[0152] Referring now to FIGS. 19 and 20, the inner snap ring 220 mayinclude at least one inner connector tab or bayonet 222 and at least oneouter connector tab 221. Referring now to FIGS. 21 and 22, the outersnap ring 230 may include at least one connector groove 211 into whichthe outer connector tab 221 of the inner snap ring 220 may be insertedso as to snap or press fit the inner snap ring 220 into place and securethe inner snap ring 220 substantially within the outer snap ring 230. Ofcourse, any suitable means for allowing the inner snap ring 220 to snapinto and be secured substantially within the outer snap ring 230 may beutilized. Referring also to FIG. 23, according to an aspect of theinvention, the inner snap ring 220 may be coupled to the outer snap ring230 by a snap or press fit connection to form a cap unit 210 (shown inFIGS. 32A and 32B). The inner connector tab 222 may be fitted into thetransducer cap connector groove 203 to allow a tight connection when thecap unit 210 is coupled with the transducer coupler 201. According to anaspect of the invention, the connection between the cap unit 210 and thetransducer coupler 201 may form a sonic connection between the absorbentpad 14 (FIG. 32A) and the transducer coupler 201. In such aconfiguration the absorbent pad 14 may be secured adjacent orsubstantially adjacent to the transducer coupler 201 (shown in FIGS. 32Athrough 32C).

[0153] Referring now to FIGS. 24A through 31, achievable results inaccordance with an aspect of the invention are illustrated.

[0154] Referring now to FIGS. 32A through 32C, a transdermal deliveryassembly according to an aspect of the present invention is illustrated.

[0155] Referring now to FIGS. 32D and 32E, achievable results inaccordance with an aspect of the invention are illustrated.

[0156] Referring now to FIG. 32E, a desktop transdermal delivery systemaccording to an aspect of the invention is illustrated.

[0157] Referring now to FIG. 32F, a belt-mounted transdermal deliverysystem according to an aspect of the invention is illustrated.

[0158] Having described the invention in the above detail, those skilledin the art will recognize that there are a number of variations to thedesign and functionality for the device, but such variations of thedesign and functionality are intended to fall within the presentdisclosure. Further, although the invention has been disclosed with acertain degree of particularity, it is understood that the presentdisclosure of the preferred forms has been made by way of example, andthat numerous changes in the details of construction and combination andarrangement of parts and steps may be made without departing from thespirit and scope of the invention as hereinafter claimed.

What is claimed is:
 1. A system being suitable for being securedsubstantially adjacent to a surface of a subject so as to effectdelivery of at least one substance through said surface and into saidsubject comprising: at least one aperture for receiving at least oneultrasonic transmission, said at least one substance being releasablysecured substantially adjacent to said at least one aperture; and, asonic member disposed with respect to said at least one aperture so asto communicate said at least one transmission to said at least onesubstance so as to effect said delivery of said at least one substancethrough said surface of said subject.
 2. The system of claim 1, furthercomprising at least one ultrasonic transducer suitable for beingpositioned substantially adjacent to said aperture so as to emitultrasonic transmissions through said aperture, and wherein areplaceable cap includes said substance, aperture and sonic member. 3.The system of claim 2, wherein said transducer comprises a plurality oftransducer elements.
 4. The system of claim 2, wherein said replaceablecap further comprises a pad substantially containing said substance andis positioned substantially between said aperture and sonic member. 5.The system of claim 1, wherein said sonic member comprises at least onematerial selected from the group consisting of saran and mylar.
 6. Thesystem of claim 4, wherein said pad comprises at least one materialselected from the group consisting of cotton, cellulose and nylon. 7.The system of claim 4, further comprising a housing defining saidaperture, coupled to said sonic member and adapted to receive said padin a snap-in manner.
 8. The system of claim 4, further comprising asemi-permeable film positioned substantially adjacent to said pad andforming an ultrasonically activated normally closed valving function tocontrol delivery of said at least one substance through said surface ofsaid subject.
 9. The system of claim 2, wherein activation of saidtransducer causes said substance to pass through said sonic member andpool upon said surface.
 10. The system of claim 2, wherein saidtransducer and cap may be worn on said surface.
 11. The system of claim2, wherein said system is as least partially secured to said surface.12. The system of claim 2, further comprising an ultrasonic transducerdriver for selectively activating said transducer according to at leastone dosing requirement.
 13. The system of claim 2, wherein saidultrasonic transmission comprises an approximately 20 to anapproximately 30 kHz, approximately 125 to approximately 225 mW/cmsignal.
 14. The system of claim 13, wherein said cap is removablycoupled to said transducer.
 15. The system of claim 14, wherein said capscrews or snaps to said transducer.
 16. The system of claim 2, whereinsaid transducer comprises a groove for facilitating securing said cap tosaid transducer.
 17. The system of claim 2, wherein said cap furthercomprises inner and outer rings coupled to one another, wherein saidinner ring includes a projection suitable for mating with said groove insaid transducer.
 18. The system of claim 2, wherein said cap comprises apad substantially containing said substance, and said cap compressessaid pad against said transducer.
 19. A system being suitable for beingsecured substantially adjacent to a surface of a subject so as to effectdelivery of at least one substance through said surface and into saidsubject comprising: a transducer housing; a plurality of ultrasonicemitters in said transducer housing; a cap defining at least oneaperture for receiving emissions from said elements; a pad releasablysecuring said at least one substance substantially adjacent to said atleast one aperture within said cap; and, a sonic member disposed withrespect to said at least one aperture so as to communicate saidemissions to said at least one pad so as to effect said delivery of saidat least one substance through said surface of said subject.
 20. Thesystem of claim 19, wherein when said cap is secured to said transducerand said system is secured to said surface, said substance is secured bysaid pad substantially adjacent to said surface.